Summary of Work: Understanding the relationships between structure and function for a DNA enzyme holds the promise of allowing us to develop specific inhibitors and other modulators of the enzyme's activity through rational design approaches. Although this idea is now fundamental in the field of structural biology, we are still in the earliest stages of bringing the approach to its full potential. Our studies of mammalian DNA polymerase beta have pioneered in the use of a coordinated approach of structural studies (x-ray crystallography, NMR, and spectroscopy), biochemical studies and genetic studies. This approach has allowed us to establish the cellular role of DNA polymerase beta in base excision repair. And, the approach has allowed us to establish a solid framework for future studies of the role of individual amino acid residues in this enzyme in such important endpoints as the speed of DNA repair, coordination of DNA synthesis with DNA ligation, coordination of dRpase with DNA synthesis, the fidelity of DNA synthesis, and the fidelity of overall DNA base excision repair. Rational drug design targeting these endpoints will allow us to strategically regulate base excision repair with DNA polymerase beta specific drugs. Detailed structure-function relationship studies of other base excision repair enzymes, such as DNA ligase I, AP endonuclease, and the various DNA glycosylases, will be undertaken in the future. Development of specific inhibitors for these enzymes will allow us to strategically de- regulate base excision repair in cells. This could have implications for chemotherapy and for understanding the role of DNA repair in preventing disease after exposure to environmental toxins. Studies of the base excision repair enzymes will enhance our understanding of other nucleic acid enzymes.